Vol.4, No.12A, 1556-1561 (2012) Health
http://dx.doi.org/10.4236/health.2012.412A 223
Obesity and obesity-related diseases: A
consequence of our man-made chemical
Eveline Dirinck1*, Philippe Jorens2, Luc Van Gaal1
1Department of Endocrinology, Diabetology and Metabolism, Antwerp University Hospital, University of Antwerp, Edegem, Bel-
gium; *Corresponding Author: Eveline.Dirinck@uza.be
2Department of Clinical Pharmacology/Toxicology, Antwerp University Hospital, University of Antwerp, Edegem, Belgium
Received 12 November 2012; revised 14 December 2012; accepted 22 December 2012
The prevalence of obesity and its related disor-
ders is currently attaining pandemic proportions,
both in the Western and the developing world.
Although lifestyle choices are commonly acce-
pted as the main reasons, it has recently been
suggested that environmental pollutants may
provide an alternative cause. Several man-made
chemicals have been shown to facilitate the dif-
ferentiation into adipocyte at environmentally
relevant levels. This process is mediated through
different nuclear receptors. The endocrine func-
tion of the adipocyte itself is also affected by
chemicals. This article provides a compact over-
view of the implicated chemicals and their mo-
des of action. We also present the current level
of evidence, linking exposure to the se endocrine
disrupting chemicals and obesity and its related
Keywords: Obesity; Diabetes; En docrine Disru pting
The prevalence of obesity is increasing at an alarming
rate throughout the world. In the United States of Amer-
ica, over 36% of the adult population is now estimated to
be overweight [1]. The conclusion that even among US
children and adolescents, obesity rates are as high as
17% is even more worrying [2]. The epidemic surpasses
national borders, with similar esti mates being reported in
European countries and now even in the developing
world [3,4]. Obesity is associated with a vast number of
diseases, such as coronary heart disease, type 2 diabetes
mellitus, some forms of cancer and even dementia [5-8].
As such, the financial cost of obesity is towering, with
type 2 diabetes mellitus alone estimated to take up 10%
of the health care costs in the developed world [9].
Traditionally, the increase in ob esity rates has been at-
tributed to an increased calorie intake and a concomitant
reduction in physical activity and energy expenditure
[10]. However, evidence has emerged recently that other
mechanisms might be involved. In 2002, Baillie-Hamil-
ton was the first to identify the coinciding increase in the
amount of man-made chemicals in our environment and
the rise in obesity prevalence [11]. Indeed, after World
War II, the production of synthetic organic chemicals has
increased exponentially each decade. These chemicals
are used in a vast array of applications, such as pesticides,
components of plastics, dyes, solvents, personal care pro-
ducts etc. Humans are exposed to them through the in-
gestion of contaminated foods and drinks, the inhalation
of polluted air or, in some cases, through trans-dermal
absorption. As a result, the average person now has ma ny
hundreds of industrial chemicals lodged in his or her
body [11]. Shortly after the large-scale introduction of
these chemicals, the first reports of reproductive health
issues in exposed wildlife surfaced [12]. Notably the in-
ferior quality of eggshells and the occurrence of abnor-
mal sex characteristics, so-called “imposex”, led to dra-
matic decreases in certain wild life species [13,14]. The se
findings sparked research into the possibility of chemi-
cals inducing endocrine disturbances. The concept “en-
docrine disruption” was defined as the inappropriate mo-
dulation of the endocrine system by dietary and envi-
ronmental chemicals: these can interfere with the synthe-
sis, secretion, transport, binding or action of natural hor-
mones in the body that are responsible for the mainte-
nance of homeostasis, reproduction, development and be-
havior [15]. To date, several types of chemicals have been
identified as endocrine disrup ting chemicals (EDC) [16].
Quite a number of these substances are very resistant to
physical, chemical and biochemical degradation, and are
Copyright © 2012 SciRes. OPEN ACCESS
E. Dirinck et al. / Health 4 (2012) 1556-1561 155 7
therefore labeled as persistent organic pollutants (POPs)
[17]. Despite the ban on production of several POPs, they
are still omnipresent in our environment. Due to their
persistency, these products travel the world, taken from
their sites of production and use by long range atmosphe-
ric transport to remote regions of our planet, thus affect-
ing virtually every person on earth [18]. For example the
Inuit, native inhabitants of Greenland, display a serum
burden of polych lorinated b iphenyls (PCBs) that is a ten-
fold higher than their counterparts in central Europe [19].
3.1. Estrogen Receptor
Although low-dose exposure to certain chemicals has
been noted to cause weight gain several decades ago, this
was initially not regard ed as problematic, or even a wan-
ted side-effect, as it was in the case of anabolic steroids
[11]. As such, this finding was often underreported or sim-
ply ignored. Initial concern about endocrine disruption fo-
cused on chemicals with estrogen-like activity. Although
adipocytes are not considered classical targets of estro-
gen, they do express functional estrogen recaptors [20].
One of the first identified estrogenic endocrine disruptors
is bisphenol A (BPA), a component of plastics [21]. In the
presence of insulin, even very low doses of bisphenol A
(2 µg/ml) are capable of stimulating the differentiation of
pre-adipocytes into mature adipocytes [22]. This finding
is intriguing, as it suggests that the exposure to environ-
mental estrogens could alter the pathway of adipocyte
development. Further research went on to show that pre-
natal and neonatal exposure to BPA in creases body w e ig h t
in animals [23,24]. Similarly, neonatal exposure of mice
to tributyltin (TBT) has been shown to increase body
weight and fat mass, an effect thought to be exerted, at
least partially, through the estr ogen receptor [25 ]. TBT is
an organotin compound, a class of products used as anti-
fouling agents, fu ngicides and heat stabilizers in plastics.
Although these endocrine disruptors have been shown to
exert their obesogenic affect through the estrogen recap-
tor, there are other, possibly more important, receptors t ar-
geted by endocri ne di sr u pt ors .
3.2. Peroxisome Proliferator-Activated
Receptor Gamma
A key factor in the process of adipogenesis is the nu-
clear receptor peroxisome proliferator-activatad receptor
gamma (PPAR-γ). Its actions are a necessity in adipocyte
differentiation and the identified target genes of PPAR
are involved in numerous aspects of lipid metabolism
and energy homeostasis [26,27]. In shor t, PPAR-γ activa-
tion increases the expression of genes that promote fatty
acid storage and represses genes that induce lipolysis in
adipocytes in white adipose tissue [28]. PPAR-γ belongs
to the nuclear receptor family of ligand-activated tran-
scription factors. The ligand binding pocket of PPAR-γ is
special since it is large and can accommodate a diversity
of chemical structures [29]. The endogenous ligands of
PPAR-γ are diverse, including prostaglandin and linoleic
acid [26]. Given the structure of its binding pocket, PPAR-
γ is known to interact with several exogenous substanc es
[29]. One of these substances is the antidiabetic drug thi-
azolidinedion e, a drug th at is linked to weight ga in in hu-
mans and increased adipogenesis in cell culture [30-32].
Tributyltin is another man-made chemical capable of ac-
tivating PPAR-γ. In vitro, even nanomolar levels act as ac-
tivators of PPAR-γ [33,34]. A TBT exposure st udy demon-
strated a significant dose-dependent increase in body
weight of young male mice, whereas prenatal exposure
to tributyltin enhances the capacity of stem cells in adult
mice white adipos e tissue to form adipocytes [35,36]. The
last group of well-known PPARγ substrates are the ph-
thalates, a group of chemicals m ost commonly used as sof-
teners for plastics [37]. Mono-(2-ethylhexyl) phtalate in
particular is an agonist for PPAR-γ and selectively acti-
vates different PPAR-γ target genes [38]. In utero expo-
sure of mice did not result in metabolic disorders in adult-
hood [39]. In humans however, the 1999-2002 National
Health And Nutrition Examination Survey, indicated th at
concentrations of several prevalent phthalate metabolites
showed a statistically significant correlation with abdomi-
nal obesity and insulin resistance. The authors provided
clinically interpretable data by stating that an increase in
phthalate metabolites fro m the 10th to the 90th percen tile,
equaled an increase in waist circumference from 3.9 to
7.8 cm, depending on the metabolite [40]. In the same
NHANES dataset, some phthalate metabolites were asso-
ciated with body mass index (BMI). These results were
most consistent in men, but less so in women [41].
3.3. Adipocytokines
Adipose tissue itself plays an active role in energy ho-
meostasis and is no longer perceived as a mere lipid sto-
rage compartment, but has evolved into an endocrine or-
gan. Adipocytokines, secr etagogues from the adipocytes,
interact functionally with many periph eral metabo lic pro-
cesses. Leptin plays a major role in the control of body
fat stores through coordinated regulation of feeding be-
haviour, metabolism, the autonomic nervous system and
body energy balance [42]. Adiponectin, another recently
described adipocyte-specific adipocytokine and a marker
of mature adipocytes, is involved in insulin sensitivity,
lipid behaviour and as such considered as the first adi-
pocytokine being potentially protective against the dia-
betogenic and atherogenic aspects of adipose tissue [43].
Several known EDC have been identified to influence ad i -
Copyright © 2012 SciRes. OPEN ACCESS
E. Dirinck et al. / Health 4 (2012) 1556-1561
pocytokine levels. Pren atal exposure of rats to diisobutyl
phthalate reduced leptin levels in both sexes while peri-
natal exposure of rats to low doses of Bisphenol A pre-
disposes to hyperleptinemia in adulthood [44,45]. This is
accompanied by a severe metabolic syndrome, includ-
ing obesity, dyslipidemia, hyperglycemia, hyperinsuline-
mia, and glucose intolerance [45]. Bisphenol A is also ca-
pable of inhibiting adiponectin release from human adi-
pocytes in vitro [46]. Taken together, exposure to EDC
might cause a metabolically unfavorable secretagogue
profile of the adipocyte.
Metabolic programming of critical tissues such as the
adipose tissue mainly takes place during foetal develop-
ment. As reviewed by Heindel and vom Saal, external ef-
fects on the developing foetus might permanently alter
metabolic pathways that are crucial for energy homeo-
stasis and thus alter the “setpoint” for developing obesity
later in life [47]. Nicotine use provides a fine example of
this theory, termed the developmental origins of ad ult di-
sease (DOAD) [48]. Smoking during pregnancy causes
direct effects, such as intrauterine growth restriction and
low birth weight, but it also predisposes to weight gain
later in life. [49]
5.1. Obesity
In vitro data and animal studies provide us with me cha -
nistic data on the obesogenic effects of endocrine disrup-
tors. Population-based epidemiological studies evaluat0
ing associations between various endocrine disruptors and
obesity have been reviewed recently [50]. Particularly in
the field of persistent organic pollutants, there have been
numerous studies published on the possible influence of
exposure to EDC early in life and the development of obe-
sity. Positive associations have been reported, although
some of these results have been difficult to replicate. For
example in utero exposure to pesticides such as DDT has
been linked to future obesity, but not in every cohort [51,
52]. Cross-sectional studies of adult exposure to certain
POPs have yielded data suggestive of a positive relatio n.
In particular the NHANES database has offered a unique
opportunity, linking exposure to PCBs and several orga-
nochlorine pesticides to obesity. [53] On the other hand,
we among many other groups have published a signifi-
cant negative correlation between BMI, waist, fat mass
percentage, total and subcutaneous abdominal adipose tis-
sue, and serum levels of some EDCs such as PCBs [54].
Combined, these results suggest that the effect of low-
dose exposure to POPs might be more complicated than
a simple obesogenic effect.
5.2. Type 2 Diabetes Mellitus, the Metabolic
Syndrome and Cardiovascular Disease
Several of the EDCs considered to be obesogenic, have
been implicated in the development of type 2 diabetes
mellitus as well, one of the most important obesity-rela-
ted diseases. The mechanisms by which these EDC cause
type 2 diabetes mellitus surpass their mere obesogenic
effect. In vitro and animal data have been accumulated
suggesting a direct effect on the pancreatic beta-cell [55].
One of the first and most notorious reports suggesting a
possible link between exposure to chemicals and type 2
diabetes mellitus has been published by the US National
Academy of Sciences’ Institute of Medicine on the US
Air Force veterans of operation Ranch Hand, responsible
for spraying defoliants during the Vietnam War. This co-
hort displays a slight but consistent increase in diabetes
incidence among subjects with elevated pesticide serum
concentrations, as well as glucose and/or insulin abnorma -
lities among all exposed individuals [56]. Ensuing studies,
in particular the ones using the database of NHANES,
have also implicated other OCPs and PCBs in the devel-
opment of type 2 diabetes [57-59]. This suggests that eve n
non-occupational, low exposure can trigger a disruption
of the glucose metabolism. Even more compelling is the
finding that serum levels of different EDCs are capable
of predicting the development of diabetes after 20 years,
as well as other dysmetabolic conditions [60]. Cross-sec-
tional analysis of the NHANES database also indicates a
clear link between several EDCs (organochlorine pesti-
cides and polychlorinated biphenyls) and the occurrence
of the metabolic syndrome in nondiabetic individuals [61].
The potential implication of EDCs in the development of
cardiovascular risk factors requires further research, con-
sidering the health burden caused by cardiovascular dis-
Interpreting the available human data on the link be-
tween en docrine d isrupting ch emicals and obesity and its
related diseases is challenging for numerous reasons.
The ultimate outcome, whether it is BMI, weight or
diabetes, is affected by a near infinite list of life style
choices (nutritional composition of the diet, exercis-
ing habits, smoking, medication…). Scrupulous data
collection is necessary in order to be able to correct
for these influences.
Some of the detected positive associations are con-
fined to subgroups, mainly determined by gender [62].
Therefore large cohorts, enabling good subgroup ana-
lysis, need to be recruited.
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E. Dirinck et al. / Health 4 (2012) 1556-1561 155 9
Most studies focus on several EDCs, thus filtering out
the effect of an individual compound can be difficult.
On the other hand, since the levels of POPs tend to be
strongly correlated, it is plausible that it is actually
the synergistic effect of several substances that causes
the ultimate observed effect.
The interpretation of cross-section al study results w ith
POPs offers particular difficulties, since the metabo-
lism of POPs is different between obese and lean in-
dividuals, with adiposity delaying the metabolism and
increasing the half-life of th ese chemicals. In general,
there are very limited d ata on the kinetics of EDC af-
ter absorption.
Unlike the more traditional toxicology, EDCs do not
always follow a monotone dose-response relationship.
Some EDCs seem to cause a strong effect at low, en-
vironmentally relevant doses, but a weakened or no
effect at high doses. This inverted U-shape associa-
tion has been suggested by some experimental studies
and further observed in epidemiological studies [59,
63]. This is problematic, as a linear dose-resp onse re-
lationship is traditionally regarded as a criterion for
causality by epidemiologists.
As suggested by the deve lopmental origin s of adult di-
sease (DOAD) theory, the time elapsing between ex-
posure to the EDC and the development of obesity c a n
extend over many years. Careful assessment of preg-
nant women and a very prolonged follow-up of their
offspring will be necessary to unravel the late conse-
quences of early-life exposure.
Finally, EDCs can induce epigenetic changes, which
are transmitted to progenity [64]. Therefore, an indi-
vidual’s susceptibility to obesog enic influences in his/
her environment, may actually be an inherited trait,
caused by EDC exposure of an ancestor.
The emerging role of endocrine disrupting chemicals
in the current pande mic of obesity and obesity-related d i-
seases is an exciting new area of interest. The presented
findings are beginning to shift the focus from the simpli-
stic notion that obesity can be understood and controlled
only by focusing of energy intake and expenditure. A vast
number of questions regarding modes of action remain to
be elucidated, and this warrants urgent further research.
The collection of data on human exposure and their ef-
fects is as crucial, despite the fact that field is burdened
with a puzzling complexity. Present data indicate a grea-
ter vulnerability to the detrimental effects of EDC in the
neonatal phase. The weight of the current evidence is
enough to prompt a precautio nary attitude towards EDC.
Given the ubiquitous dissimination of EDCs, protecting
ourselves and our offspring will require international col-
laboration on a multitud e of levels.
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